This proposal is concerned with a comprehensive approach to the study of conditions concerned with thyroid pathophysiology in man. Emphasis is placed on the development and application of a highly specific and sensitive human thyroid stimulating hormone (THS) radioimmunoassay, the study of the genesis of iodine-induced toxic goiter, the mechanism of non-triiodothyronine (T3) suppressible thyroxine (T4) secretion, source of peripheral tissue generation of T3 and reverse triiodothyronine (rT3) from T4, mechanism of impaired binding and metabolism of T4, T3 and rT3 in severe illness, expression of thyroid hormone action trhough cAMP generating systems, characterization of a serum factor responsible for pretibial myxedema, thyroid hormone metabolism in states of altered reproduction and the influence of thyroid hormone status on bone and calcium metabolism. Mathematical models for the compartmental distribution and metabolism of T3 and rT3 in normal and abnormal clinical states will be developed.